• 1. To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of clofarabine plus idarubicin, and clofarabine plus idarubicin and ara-C.
• 2. To determine the complete response rate (CR and CRp) of clofarabine plus idarubicin and ara-C vs clofarabine and ara-C vs clofarabine and idarubicin. The primary efficacy endpoint will be success defined as the number of patients achieving CR/CRp.
• 3. To compare the toxicity profiles of clofarabine plus idarubicin and ara-C vs clofarabine and ara-C vs clofarabine and idarubicin.
• 4. To compare response duration (CR/CRp) and survival of clofarabine plus idarubicin and ara-C vs clofarabine and ara-C vs clofarabine and idarubicin.

The goal of this clinical research study is to find the best safe dose for 2 different drug combinations. For this purpose, participants will either receive the combination of clofarabine plus idarubicin or clofarabine plus idarubicin and ara-C. Once the best safe dose for these drug combinations are found, the next goal is to compare the drug combinations clofarabine/idarubicin/ara-C, clofarabine/ara-C, and clofarabine/idarubicin in the treatment of patients with AML, high-grade MDS, or myeloid blast phase of CML who have relapsed following their initial therapy. In the current extension part of the study, you will only receive the clofarabine/idarubicin/ara-C combination. The activity and the safety of this treatment will be studied.

Clofarabine is a new drug that was designed to help treat leukemia. Ara-C and idarubicin are drugs that are commonly used to help treat leukemia.

Before treatment starts, you will be asked questions about your medical history and have a complete physical exam. You will have blood samples (about 1 tablespoon) collected for routine lab tests. You will either have an echocardiogram or a MUGA scan to check on the function of your heart. You will have a sample of bone marrow collected to check on the status of the disease. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. Women who are able to have children must have a negative blood or urine pregnancy test.

The first group of participants entering the study will take part in the Phase I portion of the study. The goal of the Phase I portion is to find the best safe dose for the drug combinations clofarabine plus idarubicin and clofarabine plus idarubicin and ara-C. If you are taking part in the Phase I portion of this study, you will be assigned to one of two groups. Participants in the first group will receive the combination of clofarabine and idarubicin. Participants in the second group will receive the combination of clofarabine, idarubicin, and ara-C.

For participants in the clofarabine/idarubicin group, the clofarabine will be given by vein over 1 hour once a day for 5 days in a row. Idarubicin is given by vein over 30 minutes, around one hour after clofarabine, for the first 3 days. This 5 day period is called a cycle of chemotherapy.

For participants in the clofarabine/idarubicin/ara-C group, the clofarabine will be given by vein over 1 hour once a day for 5 days in a row, on Days 2 to 6 of each cycle. Idarubicin will be given by vein over 30 minutes for 3 days in a row, on Days 1 to 3 of each cycle. Ara-C will be given by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle. Idarubicin is usually started around 1 hour after the completion of clofarabine, and ara-C about 4 hours after the start of the clofarabine infusion. This 6 day period is called a cycle of chemotherapy.

For participants in both groups, after each cycle of therapy, you will not receive the next cycle of chemotherapy until your blood counts have recovered and any possible side effects have gone away (for around 3 to 6 weeks). If the disease gets worse or side effects become too severe, treatment will stop. You must stay in Houston for the first 4 to 6 weeks (average) of treatment and are required to return to Houston to receive each additional cycle of chemotherapy (up to 6 days each cycle).

The first few participants entering the Phase I portion of the study will receive a low dose of the study drugs. The next few participants will receive a slightly higher dose of the drugs. This will continue until the best safe dose for the 2 combinations of drugs are found.

If you are taking part in the Phase I portion of the study, you will receive at least 1 cycle of therapy. If after 1-2 cycles of therapy it is found that the disease is responding to therapy, you may continue to receive therapy for up to 4 additional courses of "consolidation therapy". During the "consolidation therapy" you will also be given treatment courses with ara-C alone. When ara-C is given alone it will be given as a continuous infusion, 24 hours a day, for 5 days in a row. You will be given a portable pump so that this treatment can be done as an outpatient. The combination drug courses and the ara-C courses will alternate (ara-C alone, combination, ara-C alone, combination) for a total of 4 courses. If it is found that the disease is not responding to chemotherapy, you will be taken off the study and your doctor will discuss other treatment options with you.

Once the best safe dose of these drug combinations are found, the next group of participants entering the study will take part in the Phase II portion of the study. The goal of this part of the study is to compare the effects of the drug combinations of clofarabine/idarubicin/ara-C, clofarabine/ara-C, and clofarabine/idarubicin in the treatment of AML, MDS, and CML.

If you are taking part in the Phase II portion of the study, you will be assigned to receive treatment with clofarabine plus idarubicin and ara-C.

For participants in the clofarabine/idarubicin/ara-C group, the clofarabine will be given by vein over 1 hour once a day for 5 days in a row, on Days 2 to 6 of each cycle. Idarubicin will be given by vein over 30 minutes for 3 days in a row, on Days 1 to 3 of each cycle. Ara-C will be given by vein over 2 hours for 5 days in a row, on Days 1 to 5 of each cycle. Idarubicin is usually started around 1 hour after the completion of clofarabine, and ara-C about 4 hours after the start of the clofarabine infusion. This 6 day period is called a cycle of chemotherapy.

If you are taking part in the Phase II portion of the study, you will receive at least 1 cycle of therapy. If after 1 or 2 cycles of therapy it is found that the disease is responding to therapy, you may continue to receive therapy for up to 4 additional courses of "consolidation therapy". During the "consolidation therapy" you will also be given treatment courses with ara-C alone. When ara-C is given alone it will be given as a continuous infusion, 24 hours a day, for 5 days in a row. You will be given a portable pump so that this treatment can be done as an outpatient. The combination drug courses and the ara-C courses will alternate (ara-C alone, combination, ara-C alone, combination) for a total of 4 courses. If it is found that the disease is not responding to chemotherapy, you will be taken off the study and your doctor will discuss other treatment options with you.

The check-up visits will be the same for the participants in the Phase I and Phase II portions of the study. Before you receive each dose of drug(s), you will have a complete physical exam. During treatment, you will have blood (about 1 tablespoon) collected at least once a week during the first 2 courses of therapy, then every 2-4 weeks after. Bone marrow samples will be collected every other week during treatment to check on the status of the disease. The blood and bone marrow samples may be collected more often if your doctor feels it is necessary.

If, at any time, the disease gets worse or you experience any intolerable side effects, you will be taken off the study and your doctor will discuss other treatment options with you.

After your last course of treatment, you will have a follow-up visit scheduled. At this visit, you will have blood (about 1 tablespoon) collected for routine tests. You will have a sample of bone marrow collected to check on the status of the disease. You will also have a repeat echocardiogram or MUGA scan to check on the function of your heart.

This is an investigational study. Clofarabine has been authorized by the FDA to be used in research only. Idarubicin and ara-C are both FDA approved and are commercially available. A total of 44 patients were enrolled in the Phase I part of the study, which is now complete. Up to 120 participants will take part in the phase II part of this study. All will be enrolled at M. D. Anderson.

• Acute Myeloid Leukemia
• Myelodysplastic Syndrome
• Chronic Myeloid Leukemia

• Drug: Clofarabine
• Drug: Idarubicin
• Drug: Ara-C

Inclusion Criteria:

• Age >/= 18 years and < 60 years.
• Must be in first relapse of AML, or must receive treatment as first salvage in primary refractory AML; or have high-risk MDS (>/= 10% blasts) with not more than one prior regimen of chemotherapy (therapy with hematopoietic growth factors, biological or targeted therapies are not counted). Patients in CML myeloid blast phase may receive clofarabine as frontline therapy or in first salvage.
• Total bilirubin </= 2mg/dL, SGPT </= 4 ULN, creatinine </= 2.0mg/dL.
• ECOG performance status </= 2.
• Signed informed consent.
• Male and female patients who are fertile agree to use an effective barrier method of birth control (ie, latex condom, diaphragm, cervical cap, etc) to avoid pregnancy. Female patients need a negative serum or urine pregnancy test within 7 days of study enrollment (applies only if patient is of childbearing potential. Non-childbearing is defined as >= 1 year postmenopausal or surgically sterilized).

Exclusion Criteria:

• Previous treatment with clofarabine.
• Active, uncontrolled, systemic infection considered opportunistic, life threatening, or clinically significant at the time of treatment, or any severe, concurrent disease, which, in the judgment of the investigator and after discussion with the Principal Investigator, would make the patient inappropriate for study entry.
• Symptomatic CNS involvement.
• Patients who receive other chemotherapy. Patients must have been off previous therapy of >/= 2 weeks and must have recovered from acute toxicity of all previous therapy prior to enrollment. Treatment may start earlier following discussion with the Principal Investigator.
• Cardiac ejection fraction </= 30%.